Text assignment: Pages 79-88
Important terms to learn
Introduction: In the previous lectures on Mendelian inheritance, we have focused primarily on situations where the expected 3:1 phenotypic ratio is obtained in the F2 generation. This is the first of three lectures (based on Chapter 4 of the textbook) in which we will examine phenomena that alter the expected Mendelian ratios for a variety of reasons. This lecture concentrates on effects that involve only a single genetic locus. In the next lecture we will examine interactions among genes at two or more loci, and in lecture 10, we will examine the inheritance of genes carried on the sex chromosomes.
The nature of alleles:, If we restrict our initial analysis to independently living cells, a gene can be viewed in molecular terms as the DNA coding unit that specifies the amino acid sequence for one polypeptide chain (or in some cases, the ribonucleotide sequence of an RNA molecule that performs a biological function without being translated into protein). An allele is an alternative form of a gene. For our current purposes, we will consider only changes in genes that can cause detectable phenotypic differences.
Causes of phenotypic difference: The differences that distinguish alleles from each other can be either in the coding sequence, ranging from one base changes that cause one amino acid substitutions in the coded proteins to major deletions, insertions or rearrangements of the coding sequence, or they can be in closely linked regulatory sequences that influence how much of the gene product is synthesized. In many cases, there are multiple allleles at the same genetic locus. In such cases, the phenotypic effects that are caused by the various alleles often range from complete loss of function of the coded protein to subtle changes in function of the gene product whose effects are barely detectable.
Wild-type and mutant alleles: For many of the genetic loci in many of the species used in genetic analysis, one of the alternatives can be identified as the "wild-type" allele based on its frequency of occurrence or its arbitrary designation as "normal". In most, but not all cases, the wild-type allele will be dominant over alternatives that have been generated by mutations resulting in partial or complete loss of function. However, caution must be exercised in attempting to designate alleles as "wild-type" just because they are dominant. This is particularly true in species where substantial natural variation occurs and the mutational history responsible for the variability is not clearly understood. Examples that come to mind easily include human racial characteristics and alternative forms of agricultural species (both plant and animal) with long histories of domestication.
Hyphenation of "wild-tupe: When it is used as an adjective, as in "wild-type alllele" or "wild-type function, the term "wild-type" is always hyphenated. However, some authors use wild type as a noun without hyphenation, as in the inset items in the first column of page 81 of our textbook, whereas others claim that "wild-type phenotype" is implied in such cases and insist on always using the hyphen. We will accept either usage.
Symbols for alleles: The diversity of systems used for the naming of genetic loci and their alleles has already been called to the attention of this class in lectures 3 and 4. Our textbook discusses the naming of alleles on pages 80 and 81, but does not take as broad a view as we have in class. These notes provide an expanded view, including a summary of previous information.
Peas: Single letter designations are normally used for the limited number of genetic loci that are discussed in introductory textbooks. Upper case letters are used to designate dominant alleles and lower case for recessive alleles. There is no general agreement, however, on whether to select a letter designation that reflects the recessive phenotype or the dominant phenotype. Our textbook favors designations based on the recessive phenotype, such as D/d for tall/dwarf, W/w for round/wrinkled, and G/g for yellow/green seeds. Certain other texts favor designations based on the dominant phenotype, such as T/t for tall/dwarf, R/r for round/wrinkled, and Y/y for yellow/green seeds. Both systems are being used in this course.
Drosophila The genetic designations used for Drosophila melanogaster are organized around the way that specific mutations or alternative alleles differ from the widely accepted wild-type phenotype. Recessive mutations are named with one or a few lower case letters, and the corresponding wild-type alleles are designated as the + form. Thus, a fly that is heterozygous for the ebony mutation, e, would be designated as e +/e, or simply as +/e. Note that a slash (/) is normally inserted between the two alleles when describing a genotype in Drosophila (and many other species). Dominant alleles that cause a phenotype different from the wild-type when they are heterozygous with wild-type are designated with an upper case letter, often followed by one or more lower case letters. One such example is the curly-winged locus, Cy, located on chromosome II (for a chromsome map of Drosophila showing the locations of many different genetic loci, see Figure 5.14 on page 132 of the textbook). A heterozygous fly exhibiting the dominant curly winged phenotype would be given the genotypic designation Cy +/Cy or simply +/Cy.
Alleles that lack clearly defined dominance: In human genetics (and also in other species), a number of cases exist where there are two or more alleles at a single genetic locus that lack a clearly defined pattern of dominance (often because of codominance, described below). In such cases, an upper case letter is often used to designate the locus, with a series of superscripts (either numbers or letters) used to designate the individual alleles. Thus, for example, the locus that controls the ABO blood types contains alleles designated I A, I B, and I O.
Incomplete dominance: In the first lecture on Mendelian patterns of inheritance, we focused primarily on situations where one allele at a genetic locus was completely dominant over the alternative allele in terms of overt phenotypic expression. We now turn to situations where dominance is only partial. In such cases, the phenotype is determined by the gene dosage, with the heterozygote exhibiting an intermediate phenotype. There is apparent blending in the F1 generation, and a 1:2:1 ratio of the first parental phenotype, the intermediate phenotype, and the second parental phenotype in the F2 generation. In such cases, the F2 phenotypic distribution directly reflects the F2 genotypic ratios. An example is pink flowers on the F1 hybrid of true-breeding red-flowered and white-flowered snapdragons (Figure 4.1).
Nature of dominance: A fully dominant allele typically codes for the production of enough functional gene product so that no obvious phenotypic difference is seen when it is paired with a non-functional recessive allele. However, with the exception of a few specialized genetic loci that code for critically important proteins whose levels of expression are carefully regulated, the amount of a gene product that is produced is usually rather directly related to the number of functional alleles that are present. In extreme cases, such as the red, pink, and white flowers discussed above, the reduced level of gene product in the heterozygote is reflected in its phenotype. However, even when there is no immediately obvious phenotypic difference, the level of the gene product is likely to be substantially reduced at the biochemical level.
Tay-Sachs disease: The textbook discusses Tay-Sachs disease as an example of incomplete dominance at the biochemical level. Individuals who are homozygous for this recessive human biochemical disorder are severely affected with a lipid storage disease that is fatal within the first three years of life. The underlying biochemical defect is virtual absence of an enzyme, hexosaminidase, which is needed to prevent the abnormal lipid accumulation. Individuals who are heterozygous for this defect have about one-half of the normal level of hemoxaminadase, but this amount is enough to keep them symptom-free and healthy. Cases such as this severely blur the distinction between full and partial dominance, particularly at the more sensitive biochemical level.
Codominance: In certain cases, different alleles at the same locus result in production of detectably different gene products, with no clear pattern of dominance of one over the other. In such cases, the heterozygote will exhibit both allelic properties in a codominant manner. One example is the blood type antigens M and N, which are different forms of a glycoprotein found on the surface of red blood cells. The alleles that are involved are designated L M and L N. Homozygous individuals have type M or type N antigens on their red blood cells. Heterozygotes exhibit both antigens on their red blood cells and are designated type MN. For codominant genes in general, a cross between homozgotes results in coexpression in F1 and a 1:2:1 ratio in F2.
The A and B parts of the ABO blood group system also behave in this manner, but the picture is made more complicated by the presence of the O allele, which is recessive to both A and B, as discussed below.
Multiple alleles: Mendel dealt with either/or choices, with just 2 alleles at each genetic locus. Whenever a genetic locus is extensively studied, multiple alleles, often with intermediate phenotypic effects, can be found. These usually reflect amino acid substitutions in enzymes (or other proteins) that reduce their effectiveness, but do not totally destroy their functionality. Wild populations often contain natural distributions of 3 or more alleles, with no obvious functional advantage of one over the others.
For small numbers of alleles this can easily be verified by writing out all possibilities. Thus, if n = 4 alleles, the possible combinations are
The same result can also be obtained by using the formula:
ABO blood types: Human ABO blood types are determined by three alleles at a single locus: I A; I B and ; I O. The A and B alleles each code for variants of an enzyme that cause mutually exclusive changes to a glycolipid called H substance on the surface of red blood cells. Specifically, the enzyme coded by the IA allele adds an acetylgalactosamine residue in an exposed terminal position, whereas the IB allele codes for an altered enzymatic activity that adds a galactose residue in the same position, as shown in Figure 4.2 in the textbook. This results in the generation of two different types of antigenic properties, which are recognized by appropriate antibodies as type A and type B, respectively.
Type O: The I O allele does not code for a functional enzyme. Thus, type A and type B are both dominant over type O, and exhibit codominance to each other. There are six possible genotypes: AA, AB, BB, AO, BO, OO. Genotypes AA and AO are type A; genotypes BB and BO are type B; genotype AB is type AB; and genotype OO is type O. Human blood contains antibodies against all A/B antigens except those on its own red cells. These antibodies cause a severe reaction to transfused blood containing the target antigens. Type type O is a universal donor (but other classes of blood antigens must match) and type AB is a universal universal recipient.
Inheritance of ABO blood types: Although three different alleles are involved in the inheritance of ABO blood types, any one individual can carry only two of them. This results in a substantial number of subtly different patterns of inheritance of these blood types, as summarized in Table 4.1 on page 84 of the textbook. Perhaps the most unusual is a cross between heterozygous A/O and heterozygous B/O, which can give rise to four different phenotypes, A, B, AB, and O, in a 1:1:1:1 ratio.
Bombay phenotype: The textbook describes an additional genetic locus that has been found to affect the ABO phenotype. A woman was identified in Bombay who was phenotypically type O, despite the fact that pedigree analysis (Fig. 4.3) showed clearly that she carried the I B allele, which she received from her type AB father and passed on to two of her children. A detailed analysis revealed that she had a recessive mutation, h, at a different locus. The enzyme coded at that locus is required for the addition of a fucose residue to H substance, which must be present before the acetylgalactosamine or galactose residues can be added to generate type A or type B antigens (Figure 4.2). The recessive allele responsible for the Bombay phenotype is very rare, but it does make it possible for some individuals who are phenotypically type O to be carriers of the alleles for type A or type B.
Secretor locus: A third locus also influences ABO phenotypes. About 80% of the population carry a dominant allele that causes A and B antigens to be secreted into saliva and a variety of other body fluids. Secretion is made possible by an enzyme that further modifies the H substance to allow it to be released in a soluble form. Non-secretors lack that enzyme. The make the A and B antigens on their red blood cells, but do not secrete them.
Rh locus: The Rh blood antigens are yet another set of cell surface antigens on red blood cells. They are best known for their role in erythroblastosis fetalis, which occurs when antibodies produced by an Rh negative mother attack the red blood cells of a fetus that is Rh positive (described in greater detail on pages 624-625). There are now known to be eight subtly different Rh blood types, which are believed by some investigators to reflect 8 alternative alleles at a single locus and by others to reflect different combinations of two alleles each at three distinct but very closely linked loci (Table 4.2).
White-eyed locus in Drosophila: The white eyed locus in Drosophila is one of the more extreme examples of multiple alleles. Wild-type Drosophila have a characteristic deep red pigmentation in their eyes (Figure 4.16). The original white-eyed mutation had a complete absence of eye pigmentation. Since the original discovery of white, many other eye color mutations have been discovered and mapped to the same locus. The text claims that there are now over 100 subtly different alleles at this locus, ranging from total loss of eye pigmentation to a variety of altered shades that involve reduced levels of pigmentation (Table 4.3).
Peppered moth: The British peppered moth, Biston betularia, has 3 pigmentation alleles: M is dominant over the other two; M' is recessive to M, but dominant over m; m is recessive to the other two. This results in three phenotypes: dark (MM, MM', and Mm); intermediate (M'M', M'm); and light (mm). Recent industrialization has resulted in a sharp increase in the dark form, which is less visible on the bark of soot-covered trees (described on pages 671-672 and illustrated in Figure 24.15 on page 672).
Human HLA antigens: In certain cases the total number of possible combinations resulting from multiple alles can become extremely large. The human histocompatability antigens(pages 626-628), are coded for by multiple alleles, up to 30 per locus. In addition, there are four separate closely linked loci. Precise matching is important for organ transplantation
Pleiotropy: The term pleiotropy refers to the ability of a gene to affect more than one phenotypic characteristic. One example is human phenylketonuria, in which loss of an enzyme involved in the breakdown of excess phenylalanine causes pleiotropic effects that include elevated phenylalanine levels in the blood plasma, urinary excretion of intermediate products of phenylalanine breakdown, severely reduced IQ, changes in hair color, and changes in head size. Under close scrutiny, many genes have some degree of pleiotrophic effect. Another example, noticed by Mendel, is that the gene in peas that affected flower color (violet vs. white) also affected seed coat color and colored areas on leaves. Our textbook defines pleiotropy in the glossary of genetic terms, but does not index it, and I have not yet found where it is discussed (if it is).
Homozygous lethal alleles: Yet another disturbance of expected phenotypic ratios occurs when one of the homozygous phenotypes is lethal. One example is the Manx cat, which has no tail. The lack of a tail behaves dominantly, but there are no true-breeding lines of Manx cats. One third of the progeny of a cross between two tail-less cats have tails. It turns out that the dominant gene is a developmental defect that is lethal when homozygous and causes failure of the tail to develop when present in a single copy. Thus,
M/M is an early embryonic lethal, such that no M/M kittens are ever born. An interesting alternative interpretation of the same data is that wild type is partially dominant over the severe recessive developmental defect, such that in the heterozygote, only the tail fails to develop.
Yellow mouse: At the classic dominant yellow locus in mice, a yellow coat color (Figure 4.4 in the textbook) is dominant. However, the Y allele is lethal when homozygous.
Y/Y is an embryonic lethal. Thus, no true breeding dominant yellow mice are ever obtained. Although widely cited in textbooks as a simple dominant lethal, this is actually a more complex situation, as described below.
Deletion and gene fusion: The dominant yellow lethal allele in mice results from a deletion that includes part of the agouti (A) locus, whose function will be explained more fully in the next lecture. The deletion removes the promoter for the agouti gene and nearly all of an upstream gene in the same orientation, designated Raly, that codes for a widely expressed RNA-binding protein. The Raly promoter is left linked to the agouti gene, causing major overexpression, both in amount and location. This results in a dominant yellow phenotype, and also has pleiotropic effects, including obesity, increased size, elevated blood sugar, and increased susceptibility to cancer. The early lethal effect (before implantation) in homozygous mutant embryos is due to the complete absence of the Raly protein, and has nothing directly to do with the yellow color. There are, in fact, other dominant yellows in which agouti is overexpressed without loss of Raly. These exhibit the pleiotypic effects, but are not lethals (Michaud et al., Genes and Development 7:1203-1213, 1993).